Benzothiazole Schiff-bases as potential imaging agents for β-amyloid plaques in Alzheimer's disease

Article abstract of DOI:10.1007/s00044-012-0416-0

A series of benzothiazole Schiff-bases as potential diagnostic imaging agents targeting β-amyloid (Aβ) plaques in Alzheimer's disease (AD) were synthesized and evaluated. When in vitro binding studies using AD homogenate with [¹²⁵I] 6-iodo-2-(4

Full text of DOI:10.1007/s00044-012-0416-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0416-0
ORIGINAL RESEARCH
Benzothiazole Schiff-bases as potential imaging agents
for b-amyloid plaques in Alzheimer’s disease
•
•
•
Changsheng Gan Lin Zhou Zhenzhen Zhao
Haoshu Wang
Received: 1 June 2012 / Accepted: 11 December 2012
Ó Springer Science+Business Media New York 2012
Abstract AseriesofbenzothiazoleSchiff-basesaspotential
diagnostic imaging agents targeting b-amyloid (Ab) plaques
in Alzheimer’s disease (AD) were synthesized and evaluated.
When in vitro binding studies using AD homogenate with
b-amyloid (Ab) peptides and neurofibrillary tangles (NFTs)
formed from filaments of highly phosphorylated tau proteins
(Nordberg, 2004, 2009). The amyloid cascade hypothesis
indicates that the deposition of amyloid plaques constitutes a
central and probably early event in the pathogenesis of AD.
Therefore, the monitoring of Ab plaques would be beneficial
for the diagnosis, staging, and treatment of AD.
[
125I] 6-iodo-2-(40-dimethyl- amino)-phenyl-imidazo[1,2-
a]pyridine ([125I]IMPY) as the reference ligand were carried
out with the derivatives, the compounds showed high to low
binding affinities for AD homogenate at the Ki values ranged
from 4.38 to 514.65 nM, depending on the substitution on the
phenyl ring. Fluorescent staining in vitro showed that one
compound with a N,N-dimethylamino group intensely stained
Ab plaques within brain sections of postmortem AD patients.
The results strongly suggest that these derivatives are worthy
of further study and may be a useful amyloid imaging agents
for early detection of amyloid plaques in the brain of AD.
Presently non-invasively detection of Ab plaques using
PET and SPECT imaging tracers have been proposed as a
useful tool for early diagnosis of AD. Several promising
agents based on the backbone structure of Congo Red (CR),
thioflavin-T (ThT), and DDNP labeled with 11C, 18F, 123I
have been synthesized and evaluated for in vivo imaging
probes of Ab plaques in AD brain (Mathis et al., 2004; Cai
et al., 2007). In the last few years, clinical trials in AD
patients have been reported with several agents including
[11C]-2-(4-(methylamino)phenyl)-6-hydroxybenzothiazole
(PIB) (Mathis et al., 2003; Klunk et al., 2004), [11C]-4-N-
methylamino-40-hydroxystilbene (SB-13) (Ono et al., 2003;
Verhoeff et al., 2004), [18F]-2-(1-(2-(N-(2-fluoroethyl)-N-meth-
ylamino)naphthalene-6-yl)ethylidene)-malononitrile (FDDNP)
(Shoghi-Jadid et al., 2002), 6-iodo-2-(40-dimethyl-amino)-phe-
nyl-imidazo[1,2-a]pyridine (IMPY) (Zhuang et al., 2003;
Newberg et al., 2006), [11C]2-(2-(2-dimethylaminothiazol-5-
yl)ethenyl) -6-(2-fluoroethoxy)benzoxazole (BF-227) (Kudo
et al., 2007) (E)-4-(N-methylamino)-40-(2-(2-(2-[18F]fluoro-
ethoxy)ethoxy)ethoxy)stilbene (BAY94-9172) (Rowe et al.,
2008), 18F-florbetapir ([18F]AV-45) (Lin et al., 2010; Wong
et al., 2010) and [18F]30-F-PIB (Nelissen et al., 2009) (Fig. 1),
among which PIB is most widely studied and considered as one
of the most promising probes in AD patients.
Keywords Alzheimer’s disease ꢀ Amyloid plaques ꢀ
Benzothiazole ꢀ Schiff-bases ꢀ Binding affinity
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative
disorder and a leading cause of dementia (Selkoe, 2004;
Querfurth and LaFerla, 2010; Nestor et al., 2004). Clinical
symptoms of AD include cognitive decline, irreversible
memory loss, disorientation, language impairment, etc. AD is
characterized by abundant senile plaques (SPs) composed of
C. Gan (&) ꢀ L. Zhou ꢀ Z. Zhao ꢀ H. Wang
Engineering Research Center of Bio-process of Ministry of
Education, Hefei University of Technology, Hefei 230009,
Anhui, People’s Republic of China
The above and other studies (Kung et al., 2001; Chandra
et al., 2006; Duan and Liu, 2008; Nesterov et al., 2005)
suggest some design rules of the amyloid probes that the
molecule should be neutral and contain at least two aromatic
e-mail: gancs7894@163.com
123

Med Chem Res
NC
Fig. 1 Chemical structures of
representative amyloid imaging
agents
11CH3
NH
11CH3
NH
HO
S
N
N
CN
HO
18F
11C]PIB, 1
[
11C]SB-13, 2
[
18F]FDDNP, 3
[
O
123I
O
O
F
N
HN
O
N
N
O
N
N
S
N
18F
H311C
11C]BF-227, 5
123I]IMPY, 4
[
18F]BAY94-9172, 6
[
[
NH2
H2N
18F
O
N
O
O
HO
HN
N
N
CH3
NH
S
N
N
N
18F
-O
O
S
O
S
O
O-
18F]AV-45, 7
O
Congo Red, 9
[
18F]3'-F-PIB, 8
[
rings and a linker, and moreover, the presence of hydro-
phobic planarizable (or easily planarizable) conjugate sys-
tem is an important design feature to obtain high binding
affinity. The structure of stilbene is common in the reported
by direct condensation of benzothiazole with different
benzaldehyde under the catalysis of acidic catalyst. By
screening the catalyst, acetic acid, p-toluenesulfonic acid,
and other Lewis acids, such as anhydrous ZnCl2, we
selected HOAc as the appropriate catalyst. The reaction
could be smoothly carried out under equivalent HOAc in
reflux EtOH with different substrates.
imaging agents. In a previous literature (Lee et al., 2001),
stilbene with double bond of C and C may isomerize in
certain circumstance. Congo Red is one of the most fre-
quently used imaging agents in the postmortem detection of
AD patients, whose structure contains two double bonds of N
and N. However, to our knowledge, Schiff-base with double
bond of C and N is scarcely reported as the amyloid imaging
agent. In this article, we designed a novel series of benzo-
thiazole Schiff-bases (compound 12 in Scheme 1) with the
key structure or pharmacophore of PIB and double bond of C
and N as the linker. The compounds were synthesized and
evaluated with postmortem AD homogenate. Compounds
12a and 12c exhibited high binding properties, which can be
further radiolabeled by C-11 or F-18 to be used for in vivo
imaging of amyloid plaques in AD (Manook et al., 2012;
Neumaier et al., 2010; Yousefi et al., 2011).
Biological evaluation
In vitro binding assay
The binding affinities (Ki) of the benzothiazole Schiff-
bases were evaluated by radioligand competition binding
assay with [125I]IMPY for Ab plaques using homogenates
prepared from postmortem AD brain tissues. [125I]IMPY
was prepared as described previously (Zhuang et al., 2003).
The results are shown in Table 1.
The binding properties changed greatly while the sub-
stituents varied. In the case of 12b, where the phenyl rings
carry strongly electron-withdrawing NO2 groups (R =
NO2), the Ki was found to be 514.65 nM. However, the
replacement of the NO2 groups with NMe2 (compound 12a)
or OMe (compound 12c) resulted in a steep decrease in the Ki
value (4.38 and 10.82 nM, respectively). It proves that the
phenyl rings should be electron rich in order for these com-
pounds to exhibit high binding affinities. For compounds 12d
and 12e, when substituent R is changed from Br to I, only low
Results and discussion
Chemistry
The synthesis of the benzothiazole Schiff-bases is outlined
in Scheme 1. The target compounds were easily prepared
Scheme 1 Synthesis of benzothiazole
Schiff-bases
cat
S
N
S
N
H3CO
H3CO
+ OHC
R
N
C
R
NH2
H
CH3CH2OH
10
11
12
a R = N(CH3)2
b R = NO2
c R = CH3O
d R = Br
a R = N(CH3)2
b R = NO2
c R = CH3O
d R = Br
e R = I
e R = I
f R=OH
f R=OH
123

Med Chem Res
Experimental section
Table 1 Inhibition constants (Ki) of compound 12 on ligand
binding to AD brain homogenates
Materials and instruments
Entry
Compounds
Ki (nM)
4.38 0.41
1
12a
12b
12c
12d
12e
12f
The reagents used in the syntheses were purchased from
Alfa Aesar, Sigma-Aldrich and Sinopharm Chemical Reagent
Co. Ltd and were used without further purification unless
otherwise indicated. The AD human brain homogenates
and paraffin brain sections were obtained from the Neth-
2
514.65 53.37
10.82 1.30
106.46 8.63
102.74 6.88
34.72 2.87
5.30 0.36
3
4
5
1
6
erlands brain bank (coordinator: Dr. I. Huitinga). The H
IMPY
NMR spectra were obtained on a Bruker Avance-500
(500 MHz) spectrometer with TMS as the internal stan-
dard. FT-IR spectra were obtained on a Thermo Scientific
Nicolet 8700 system.
Values are the mean for three independent experiments
binding affinities were obtained with insignificant differ-
ence. Compound 12f with substituent R as OH also showed a
good binding property with Ki value of 34.72 nM.
General procedure for the preparation
of the benzothiazole Schiff-bases
Combined with the previous reports (Carter and Chou,
1998; Klunk et al., 1999), some clues can be inferred from
the results. The binding affinity is largely due to the
hydrogen bond, hydrophobic interaction, p–p stacking, and
electrostatic interaction between the ligand and the target
protein. All the investigated compounds bearing benzo-
thiazole and phenyl ring can form p–p stacking or hydro-
phobic interaction with the amyloid peptides. Compounds
12a, 12c, and 12f exhibited higher binding properties,
probably because of its substituents, which can form
hydrogen bond with the amyloid aggregates more easily.
The structure bearing electron-rich aromatic rings is more
favorable for binding properties possibly owing to the
stronger interaction of p–p stacking.
To a mixture of 2-amino-5-methoxybenzothiazole (1 mmol)
and different substituted benzaldehyde (1 mmol) in 10 mL
of anhydrous ethanol was added to acetic acid (1 mmol)
dropwise. The reaction mixture was refluxed for 18 h. After
cooling to room temperature, the precipitate was filtered to
give an orange (12a, 12b) or yellow solid (12c–12f), which
was purified by silica gel chromatography to give the desired
products (12a–12f).
12a
1H-NMR (300 MHz, CDCl3) d 8.80 (s, 1H), 7.88 (d, 2H,
J = 9.0 Hz), 7.80 (d, 1H, J = 8.9 Hz), 7.27 (d, 1H, J =
2.6 Hz), 7.03 (dd, 1H, J = 2.6, 8.9 Hz), 6.73 (d, 2H,
J = 9.0 Hz), 3.88 (s, 3H), 3.10 (s, 6H). IR (cm-1) 3033,
2938, 2832, 1603, 1577, 1471, 1230, 1167, 1061, 839.
AD brain tissue fluorescent staining
As these benzothiazole derivatives could emit fluorescence
well, the AD brain tissue fluorescent staining was further
performed for visually investigating the binding ability of
these compounds to the SPs in vitro. As shown in Fig. 2,
almost all the SPs in the brain section were labeled by ligand
12a (B1), as confirmed by staining with thioflavin S (ThS,
A1) in the adjacent section as compared to the blank control
section (C1). Details of SP staining could be clearly visu-
alized by the fluorescence of 12a (B2), while the staining
pictures in the red rectangle were expanded as shown in the
bottom row of Fig. 2. Hollow arrow refers to the SPs.
Interestingly, similar to ThS (A2), the NFTs, as indicated by
triangle arrows in Fig. 2, could also be labeled by 12a (B2).
The binding properties of both amyloid plaques and tangles
as FDDNP suggest it may be potentially helpful in the
diagnosis of Alzheimer’s disease and mild cognitive
impairment (Petersen et al., 2006; Guillozet et al., 2003;
Small et al., 2006; Barrio et al., 2008; Shin et al., 2008).
12b
1H-NMR (300 MHz, CDCl3) d 9.15 (s, 1H), 8.36 (d, 2H, J =
8.8 Hz), 8.19 (d, 2H, J = 8.8 Hz), 7.90 (d, 1H, J = 9.0 Hz),
7.33 (d, 1H, J = 2.5 Hz), 7.12 (dd, 1H, J = 2.5, 9.0 Hz),
3.91 (s, 3H). IR (cm-1) 3066, 2941, 2836, 1601, 1558, 1513,
1483, 1342, 1220, 844.
12c
1H-NMR (300 MHz, CDCl3) d 8.92 (s, 1H), 7.97 (d, 2H,
J = 8.8 Hz), 7.84 (d, 1H, J = 8.9 Hz), 7.29 (d, 1H, J =
2.6 Hz), 7.06 (dd, 1H, J = 2.6, 8.9 Hz), 7.01 (d, 2H, J =
8.8 Hz), 3.90 (s, 3H), 3.89 (s, 3H). IR (cm-1) 3006, 2965,
2934, 1603, 1565, 1424, 1262, 1145, 1051, 1022, 838.
123

Med Chem Res
Fig. 2 Three adjacent AD brain sections were stained (a ThS, b 12a, c blank control). The hollow arrows indicate the amyloid plaques. The
triangle arrows indicate the neurofibrillary tangles. The bottom row was the magnified images of the boxed area in the top row. Bar 250 lm
(Color figure online)
12d
approximately 100-mg wet tissue/mL using a motor-driven
homogenizer (Glas-Col, USA). The homogenates were
aliquoted into 1-mL portions and stored at -80 °C. For
binding assays, the homogenates were thawed, diluted with
ice-cold PBS solution (0.05 M, pH 7.4), and homogenized
again using an ice-cold hand-held glass homogenizer.
1H-NMR (300 MHz, CDCl3) d 8.97 (s, 1H), 7.87 (m, 3H),
7.66–7.64 (m, 2H), 7.30 (m, 1H), 7.10–7.07 (m, 1H), 3.89
(s, 3H). IR (cm-1) 3013, 2968, 2940, 1602, 1586, 1484,
1267, 1228, 1057, 847.
12e
In vitro binding assays with AD brain homogenates
1H-NMR (300 MHz, CDCl3) d 8.96 (s, 1H), 7.89–7.86 (m,
3H), 7.72 (d, 2H, J = 8.3 Hz), 7.30 (d, 1H, J = 2.3 Hz),
Radioligand competition binding assays were carried out
in 12 9 75 mm borosilicate glass tubes. To a glass tube
AD brain homogenates (100 lL), 0.05 nM radioligand
7.08 (dd, 1H, J = 2.3, 8.9 Hz), 3.89 (s, 3H). IR (cm-1
)
3073, 2936, 2829, 1614, 1555, 1495, 1264, 1224, 1054,
865.
[
125I]IMPY (100 lL), inhibitor (100 lL, 3 9 10-6 to
1 9 10-10 M), and 0.05 M PBS (pH 7.4, 700 lL) were
added to bring the final volume to 1 mL. Non-specific
binding was defined in the presence of 600-nM IMPY in the
same assay tubes. The mixture was incubated at 37 °C for
2 h, and the bound and the free radioactivity were separated
by vacuum filtration through Whatman GF/B filters using a
ZT-II-12R cell harvester followed by 2 9 3 mL washes of
PBS at room temperature. Filters containing the bound I-125
ligand were counted in a gamma counter (USTC Zonkia GC-
1200, Hefei, China) with a 65 % counting efficiency. Values
for the half-maximal inhibition concentration (IC50) were
computed from displacement curves of three independent
experiments using GraphPad Prism 5. In addition, the inhi-
bition constant (Ki) was calculated using the Cheng–Prusoff
equation: Ki = IC50/(1 ? [L]/Kd), where [L] is the concen-
tration of radioligand used in the assay, and Kd is the disso-
ciation constant of radioligand.
12f
1H-NMR (300 MHz, CDCl3) d 8.98 (s, 1H), 7.94 (d, 2H,
J = 8.6 Hz), 7.79 (d, 1H, J = 8.9 Hz), 7.63 (d, 1H, J =
2.4 Hz), 7.10 (dd, 1H, J = 2.4, 8.9 Hz), 6.96 (d, 2H,
J = 8.6 Hz), 3.85 (s, 3H). IR (cm-1) 3033, 2939, 1603,
1578, 1523, 1471, 1269, 1230, 1167, 839.
Preparation of brain tissue homogenates
Frozen AD brain tissues were thawed and placed on ice.
The gray and white matters were dissected, weighed, and
homogenized in ice-cooled phosphate buffered saline
(PBS) solution (0.05 M, pH 7.4) at a concentration of
123

Med Chem Res
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AD brain tissue fluorescent staining
Brain tissues were obtained from autopsy-confirmed AD
subjects. Adjacent tissue sections (6 lm thickness) were
processed for staining. First, the paraffin brain sections were
treated with 2 9 10 min washes in xylene, 2 9 10 min
washes in 100 % ethanol, 5-min sequential washes in 95, 90,
80, and 70 % ethanol, and sequential rinsings (5 min each) in
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washing in PBS. Quenched brain tissue sections were
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Third, the sections were differentiated by 50 % EtOH/H2O
for 10 min (cold ligand), or 70 % EtOH/H2O for 10 min
(ThS). Finally, the sections were washed in PBS (3 9 5 min)
and sealed by 80 % glycerin/PBS and cover-slips. These
sections were stored at 4 °C in darkness and viewed using an
Olympus IX71 fluorescence microscope (Olympus, Tokyo)
with an SPOT digital camera (Diagnostic Instruments,
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Conclusions
model of Alzheimer’s disease. PLoS ONE 7(3):e31310. doi:
10.1371/journal.pone.0031310
A series of benzothiazole Schiff-bases were readily pre-
pared and compounds 12a, 12c, 12f exhibited high binding
affinities to amyloid plaques in AD brain. These derivatives
with high affinities provide the possibility of a scaffold for
potential molecular imaging agents to monitor Ab plaques
in the brain of AD patients.
Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE
(2003) Synthesis and evaluation of 11C-labeled 6-substituted
2-arylbenzothiazoles as amyloid imaging agents. J Med Chem
46:2740–2754
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plaques and neurofibrillary tangles in the aging human brain.
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Function and Disease, Chinese Academy of Sciences for financial
support.
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TM (2005) In vivo optical imaging of amyloid aggregates in
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